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Article ; Online: Heads or tails: making the spinal cord.

Needham, Julia / Metzis, Vicki

2022 Volume 485, Page(s) 80–92

Abstract: The central nervous system contains a vast array of cell types that are produced along the length of the rostrocaudal axis. This diversity in cell identity is established during embryonic development, and ensures that physiologically distinct cell types ... ...

Abstract	The central nervous system contains a vast array of cell types that are produced along the length of the rostrocaudal axis. This diversity in cell identity is established during embryonic development, and ensures that physiologically distinct cell types develop in the appropriate position in the body. Understanding how this cellular diversity arises remains a major challenge central to the field of developmental biology. In more recent years, approaches using pluripotent embryonic stem cells (ESCs) as in vitro models of development have revealed many insights into nervous system regionalisation. Here, we outline advances in the directed differentiation of ESCs, focusing on the generation of the spinal cord. We discuss the regionalisation events that impact the caudal part of the nervous system, highlighting general principles underpinning rostrocaudal differences within the mammalian body plan.
MeSH term(s)	Animals ; Cell Differentiation ; Embryonic Stem Cells ; Gene Expression Regulation, Developmental ; Homeodomain Proteins/metabolism ; Mammals/metabolism ; Spinal Cord
Chemical Substances	Homeodomain Proteins
Language	English
Publishing date	2022-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2022.03.002
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Article: Heads or tails: making the spinal cord

Needham, Julia / Metzis, Vicki

Developmental biology. 2022 May, v. 485

2022

Abstract	The central nervous system contains a vast array of cell types that are produced along the length of the rostrocaudal axis. This diversity in cell identity is established during embryonic development, and ensures that physiologically distinct cell types develop in the appropriate position in the body. Understanding how this cellular diversity arises remains a major challenge central to the field of developmental biology. In more recent years, approaches using pluripotent embryonic stem cells (ESCs) as in vitro models of development have revealed many insights into nervous system regionalisation. Here, we outline advances in the directed differentiation of ESCs, focusing on the generation of the spinal cord. We discuss the regionalisation events that impact the caudal part of the nervous system, highlighting general principles underpinning rostrocaudal differences within the mammalian body plan.
Keywords	embryogenesis ; mammals ; spinal cord
Language	English
Dates of publication	2022-05
Size	p. 80-92.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2022.03.002
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Article ; Online: Building consensus in neuromesodermal research: Current advances and future biomedical perspectives.

Binagui-Casas, Anahí / Dias, André / Guillot, Charlène / Metzis, Vicki / Saunders, Dillan

Current opinion in cell biology

2021 Volume 73, Page(s) 133–140

Abstract: The development of the vertebrate body axis relies on the activity of different populations of axial progenitors, including neuromesodermal progenitors. Currently, the term 'Neuromesodermal progenitors' is associated with various definitions. Here, we ... ...

Abstract	The development of the vertebrate body axis relies on the activity of different populations of axial progenitors, including neuromesodermal progenitors. Currently, the term 'Neuromesodermal progenitors' is associated with various definitions. Here, we use distinct terminologies to highlight advances in our understanding of this cell type at both the single-cell and population levels. We discuss how these recent insights prompt new opportunities to address a range of biomedical questions spanning cancer metastasis, congenital disorders, cellular metabolism, regenerative medicine, and evolution. Finally, we outline some of the major unanswered questions and propose future directions at the forefront of neuromesodermal research.
MeSH term(s)	Body Patterning ; Consensus ; Mesoderm
Language	English
Publishing date	2021-10-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2021.08.003
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Article ; Online: Sox2 levels regulate the chromatin occupancy of WNT mediators in epiblast progenitors responsible for vertebrate body formation.

Blassberg, Robert / Patel, Harshil / Watson, Thomas / Gouti, Mina / Metzis, Vicki / Delás, M Joaquina / Briscoe, James

Nature cell biology

2022 Volume 24, Issue 5, Page(s) 633–644

Abstract: WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by the transcription ... ...

Abstract	WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. Here we provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 displaces nucleosomes from regulatory elements with high-affinity SOX2 binding sites, recruiting the WNT effector TCF/β-catenin and maintaining pluripotent gene expression. Reducing SOX2 levels destabilizes pluripotency and reconfigures SOX2/TCF/β-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT-induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/β-catenin and reveal how context-specific responses to a signal are configured by the level of a transcription factor.
MeSH term(s)	Animals ; Chromatin ; Mesoderm/metabolism ; Transcription Factors ; Vertebrates/metabolism ; beta Catenin/genetics ; beta Catenin/metabolism
Chemical Substances	Chromatin ; Transcription Factors ; beta Catenin
Language	English
Publishing date	2022-05-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-022-00910-2
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Article ; Online: ERK1/2 signalling dynamics promote neural differentiation by regulating chromatin accessibility and the polycomb repressive complex.

Semprich, Claudia I / Davidson, Lindsay / Amorim Torres, Adriana / Patel, Harshil / Briscoe, James / Metzis, Vicki / Storey, Kate G

PLoS biology

2022 Volume 20, Issue 12, Page(s) e3000221

Abstract: Fibroblast growth factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress, FGF signalling must decline. ... ...

Abstract	Fibroblast growth factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress, FGF signalling must decline. Why these signalling dynamics are required has not been determined. Here, we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos, and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs genome-wide across neural genes. Importantly, ERK1/2 inhibition induces precocious neural gene transcription, and this involves dissociation of the polycomb repressive complex from key gene loci. This takes place independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. Transient ERK1/2 inhibition is sufficient for the dissociation of the repressive complex, and this is not reversed on resumption of ERK1/2 signalling. Moreover, genomic footprinting of sites identified by ATAC-seq together with ChIP-seq for polycomb protein Ring1B revealed that ERK1/2 inhibition promotes the occupancy of neural transcription factors (TFs) at non-polycomb as well as polycomb associated sites. Together, these findings indicate that ERK1/2 signalling decline promotes global changes in chromatin accessibility and TF binding at neural genes by directing polycomb and other regulators and appears to serve as a gating mechanism that provides directionality to the process of differentiation.
MeSH term(s)	Mice ; Humans ; Animals ; Chromatin ; MAP Kinase Signaling System ; Polycomb-Group Proteins/genetics ; Polycomb-Group Proteins/metabolism ; Cell Differentiation ; Signal Transduction
Chemical Substances	Chromatin ; Polycomb-Group Proteins
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3000221
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Article ; Online: Precision of tissue patterning is controlled by dynamical properties of gene regulatory networks.

Exelby, Katherine / Herrera-Delgado, Edgar / Perez, Lorena Garcia / Perez-Carrasco, Ruben / Sagner, Andreas / Metzis, Vicki / Sollich, Peter / Briscoe, James

Development (Cambridge, England)

2021 Volume 148, Issue 4

Abstract: During development, gene regulatory networks allocate cell fates by partitioning tissues into spatially organised domains of gene expression. How the sharp boundaries that delineate these gene expression patterns arise, despite the stochasticity ... ...

Abstract	During development, gene regulatory networks allocate cell fates by partitioning tissues into spatially organised domains of gene expression. How the sharp boundaries that delineate these gene expression patterns arise, despite the stochasticity associated with gene regulation, is poorly understood. We show, in the vertebrate neural tube, using perturbations of coding and regulatory regions, that the structure of the regulatory network contributes to boundary precision. This is achieved, not by reducing noise in individual genes, but by the configuration of the network modulating the ability of stochastic fluctuations to initiate gene expression changes. We use a computational screen to identify network properties that influence boundary precision, revealing two dynamical mechanisms by which small gene circuits attenuate the effect of noise in order to increase patterning precision. These results highlight design principles of gene regulatory networks that produce precise patterns of gene expression.
MeSH term(s)	Animals ; Biomarkers ; Body Patterning/genetics ; Embryonic Development ; Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Mice ; PAX6 Transcription Factor/genetics ; PAX6 Transcription Factor/metabolism ; Regulatory Sequences, Ribonucleic Acid
Chemical Substances	Biomarkers ; PAX6 Transcription Factor ; Pax6 protein, mouse ; Regulatory Sequences, Ribonucleic Acid
Language	English
Publishing date	2021-02-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.197566
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Article ; Online: Unmasking the ciliopathies: craniofacial defects and the primary cilium.

Cortés, Claudio R / Metzis, Vicki / Wicking, Carol

Wiley interdisciplinary reviews. Developmental biology

2015 Volume 4, Issue 6, Page(s) 637–653

Abstract: Over the past decade, the primary cilium has emerged as a pivotal sensory organelle that acts as a major signaling hub for a number of developmental signaling pathways. In that time, a vast number of proteins involved in trafficking and signaling have ... ...

Abstract	Over the past decade, the primary cilium has emerged as a pivotal sensory organelle that acts as a major signaling hub for a number of developmental signaling pathways. In that time, a vast number of proteins involved in trafficking and signaling have been linked to ciliary assembly and/or function, demonstrating the importance of this organelle during embryonic development. Given the central role of the primary cilium in regulating developmental signaling, it is not surprising that its dysfunction results in widespread defects in the embryo, leading to an expanding class of human congenital disorders known as ciliopathies. These disorders are individually rare and phenotypically variable, but together they affect virtually every vertebrate organ system. Features of ciliopathies that are often overlooked, but which are being reported with increasing frequency, are craniofacial abnormalities, ranging from subtle midline defects to full-blown orofacial clefting. The challenge moving forward is to understand the primary mechanism of disease given the link between the primary cilium and a number of developmental signaling pathways (such as hedgehog, platelet-derived growth factor, and WNT signaling) that are essential for craniofacial development. Here, we provide an overview of the diversity of craniofacial abnormalities present in the ciliopathy spectrum, and reveal those defects in common across multiple disorders. Further, we discuss the molecular defects and potential signaling perturbations underlying these anomalies. This provides insight into the mechanisms leading to ciliopathy phenotypes more generally and highlights the prevalence of widespread dysmorphologies resulting from cilia dysfunction.
MeSH term(s)	Animals ; Cilia/pathology ; Craniofacial Abnormalities/pathology ; Embryonic Development/physiology ; Humans ; Phenotype ; Signal Transduction/physiology
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1759-7692
ISSN (online)	1759-7692
DOI	10.1002/wdev.199
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Article: The route to spinal cord cell types: a tale of signals and switches.

Gouti, Mina / Metzis, Vicki / Briscoe, James

Trends in genetics : TIG

2015 Volume 31, Issue 6, Page(s) 282–289

Abstract: Understanding the mechanisms that control induction and elaboration of the vertebrate central nervous system (CNS) requires an analysis of the extrinsic signals and downstream transcriptional networks that assign cell fates in the correct space and time. ...

Abstract	Understanding the mechanisms that control induction and elaboration of the vertebrate central nervous system (CNS) requires an analysis of the extrinsic signals and downstream transcriptional networks that assign cell fates in the correct space and time. We focus on the generation and patterning of the spinal cord. We summarize evidence that the origin of the spinal cord is distinct from the anterior regions of the CNS. We discuss how this affects the gene regulatory networks and cell state transitions that specify spinal cord cell subtypes, and we highlight how the timing of extracellular signals and dynamic control of transcriptional networks contribute to the correct spatiotemporal generation of different neural cell types.
MeSH term(s)	Animals ; Body Patterning/genetics ; Central Nervous System/cytology ; Central Nervous System/embryology ; Central Nervous System/metabolism ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Germ Layers/cytology ; Germ Layers/embryology ; Germ Layers/metabolism ; Humans ; Models, Genetic ; SOXB1 Transcription Factors/genetics ; Spinal Cord/cytology ; Spinal Cord/embryology ; Spinal Cord/metabolism
Chemical Substances	SOXB1 Transcription Factors
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2015.03.001
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Article: Nervous System Regionalization Entails Axial Allocation before Neural Differentiation

Metzis, Vicki / Steinhauser, Sebastian / Pakanavicius, Edvinas / Gouti, Mina / Stamataki, Despina / Ivanovitch, Kenzo / Watson, Thomas / Rayon, Teresa / Mousavy Gharavy, S. Neda / Lovell-Badge, Robin / Luscombe, Nicholas M / Briscoe, James

Cell. 2018 Nov. 01, v. 175, no. 4

2018

Abstract: Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to ... ...

Abstract	Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This “primary regionalization” allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS.
Keywords	brain ; chromatin ; embryonic germ layers ; models ; neurons ; spinal cord ; vertebrates
Language	English
Dates of publication	2018-1101
Size	p. 1105-1118.e17.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2018.09.040
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Article ; Online: Nervous System Regionalization Entails Axial Allocation before Neural Differentiation.

Metzis, Vicki / Steinhauser, Sebastian / Pakanavicius, Edvinas / Gouti, Mina / Stamataki, Despina / Ivanovitch, Kenzo / Watson, Thomas / Rayon, Teresa / Mousavy Gharavy, S Neda / Lovell-Badge, Robin / Luscombe, Nicholas M / Briscoe, James

Cell

2018 Volume 175, Issue 4, Page(s) 1105–1118.e17

Abstract	Neural induction in vertebrates generates a CNS that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity; caudalizing signals then convert a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations, this identified a developmental time window in which genome-wide chromatin-remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This "primary regionalization" allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate CNS.
MeSH term(s)	Animals ; Cell Line ; Cells, Cultured ; Chick Embryo ; Chromatin Assembly and Disassembly ; Embryonic Induction ; Female ; Gene Expression Regulation, Developmental ; Male ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neurogenesis ; Spinal Cord/cytology ; Spinal Cord/growth & development ; Spinal Cord/metabolism
Language	English
Publishing date	2018-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2018.09.040
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